Methods for producing oxirane carboxylic acids and derivatives thereof

ABSTRACT

The invention relates to processes for preparing oxiranecarboxylic acids and derivatives thereof, in particular to processes which proceed under stereochemical control of the reaction steps, to the oxiranecarboxylic acids prepared according to the invention and derivatives thereof and to their use in pharmaceutical compositions, in particular for treating hyperlipaemia.

[0001] The invention relates to processes/methods forpreparing/producing oxiranecarboxylic acids and derivatives thereof, tothe oxiranecarboxylic acids prepared according to the invention and totheir use in pharmaceutical compositions.

[0002] Hitherto, oxiranecarboxylic acids and derivatives thereof havebeen used, for example, for treating cardiac insufficiency and coronaryheart disease, as described, for example, in WO 95/15161, or else fortreating diabetes (WO 82/00645). (+)-Etomoxir, in particular, issuitable for treating hyperlipaemia.

[0003] The processes described in the literature for preparingoxiranecarboxylic acids and derivatives thereof can only be carried outon a laboratory scale, so that the oxiranecarboxylic acids andderivatives thereof can not be provided in sufficient amounts at lowcost.

[0004] EP-A 0 386 654 describes a process for preparing racemicoxiranecarboxylic acids which have to be separated after the synthesisto yield the pure enantiomers.

[0005] A key step in the synthesis of oxiranecarboxylic acids is theconstruction of the stereocentre and the cyclization to give theoxirane. In the literature, various processes have been described forthis purpose. Thus, for example, the publication “Asymmetrization of2-substituted glycerols: Syntheses of R-Etomoxir and R-Palmoxirate” byK. Prasad et al., Tetrahedron: Asymmetry, 1990, 1, 421-424, describes asynthesis starting from 2-substituted glycerol involving anenantioselective hydrolysis with the use of hydrolytic enzymes. Theyield of the key step is about 45%.

[0006] EP-B 0 046 590 describes a process for preparingphen(alk)oxy-substituted oxiranes in which the oxirane is introducedinto the molecule by oxidation of a C—C double bond. The crude productthen requires a complicated chromatographic purification.

[0007] M. M. H. Crilley et al. (Tetrahedron Lett., 1989, 30, 885)describe a synthesis involving a sharpless epoxidation, with a yield of49% in this key step.

[0008] The article “Asymmetric synthesis of (R)-(+)-etomoxir” by S. Jewet al., Tetrahedron: Asymmetry, 1997, 8, 1187-1192, describes a 10-stepsynthesis which yields etomoxir in amounts of 30 mg. The synthesisemploys diazomethane, which renders this process unsuitable for alarge-scale synthesis. In addition, in this synthesis, the substituenton the side-chain is modified after the cyclization to the oxirane, i.e.after the construction of the stereocentre. This means that even duringthe further course of the reaction, the stereochemistry has to bestrictly controlled to avoid complicated purification steps andseparation problems.

[0009] None of the processes hitherto utilized for preparingoxiranecarboxylic acids and derivatives thereof is suitable for alarge-scale synthesis, in particular since expensive and dangerousstarting materials or auxiliaries are employed and since thestereochemistry has to be controlled over a large number of synthesissteps.

[0010] Accordingly, it was the primary object of the present inventionto provide a process for preparing oxiranecarboxylic acids andderivatives thereof where a synthesis is carried out on an industrialscale using inexpensive raw materials obtainable in a simple manner andin large amounts.

[0011] According to the invention, this object is achieved by a processfor preparing oxiranecarboxylic acids and derivatives thereof,comprising the synthesis of a compound of the formula (VIII)

[0012] in which

[0013] R¹ is a straight-chain or branched mono-, poly- or unsubstitutedalkyl group, a straight-chain or branched mono-, poly- or unsubstitutedalkylene group, a straight-chain or branched mono-, poly- orunsubstituted aralkyl, alkylaryl or aryl group,

[0014] the radicals R⁴ and R⁵ are identical or different straight-chainor branched mono-, poly- or unsubstituted alkyl groups, straight-chainor branched mono-, poly- or unsubstituted alkylene groups,straight-chain or branched mono-, poly- or unsubstituted aralkyl,alkylaryl or aryl groups, where R⁴NCR⁵ may be part of a substituted orunsubstituted cyclic structure which may also contain a furtherheteroatom selected from the group consisting of N, S and O,

[0015] X⁴ is a functional group capable of forming a cationicintermediate in a reaction with a C—C double bond and is a good leavinggroup, and

[0016] R¹ and R⁴NCR⁵ are not simultaneously —(CH₂)₆—OBn and anunsubstituted five-membered ring, respectively,

[0017] comprising the steps

[0018] (a) of reacting a compound of the formula (V) with an amine ofthe formula (VI) to give a compound of the formula (VII)

[0019] in which the radicals R¹, R⁴ and R⁵ are as defined above; and

[0020] (b) converting a compound of the formula (VII) into a lactone ofthe formula (VIII).

[0021] A particular advantage of the process according to the inventionis the fact that oxiranecarboxylic acids and derivatives thereof can beprepared on an industrial scale, i.e. on a kilogram scale.

[0022] In the context of the present invention, oxiranecarboxylic acidsand derivatives thereof are understood as meaning oxiranecarboxylicacids of the formula (X) and their esters with C1- to C15-alcohols andthe pharmacologically acceptable salts of the carboxylic acids. Suitablesalts are salts with inorganic and organic bases. Cations suitable foruse in the salt formation are especially the cations of the alkalimetals, alkaline earth metals or earth metals. Salts of lithium, sodium,potassium, magnesium, calcium and aluminium may be mentioned by way ofexample. However, it is also possible to use the corresponding cationsof organic nitrogen bases, such as amines, amino alcohols, amino sugars,basic amino acids, etc. Salts of ethylenediamine, dimethylamine,diethylamine, morpholine, piperidine, piperazine, N-methylpiperazine,methylcyclohexylamine, benzylamine, ethanolamine, diethanolamine,triethanolamine, tris(hydroxymethyl)-aminoethane,2-amino-2-methylpropanol, 2-amino-2-methyl-1,3-propanediol, glucamine,N-methylglucamine, glucosamine, N-methylglucosamine, lysine, ornithine,arginine and quinoline may be mentioned by way of example.

[0023] For the reaction according to step (a), the carboxylic acid ofthe formula (V) is preferably initially activated. An activation can becarried out, for example, by forming a carboxylic anhydride, anactivated carboxylic ester or a carbonyl halide. For the industrialsynthesis in the context of the present invention, activation ascarbonyl chloride is particularly preferred.

[0024] The compound of the formula (V) is reacted with a suitablereagent capable of forming carbonyl chlorides, such as, for example, anorganic or inorganic acid chloride. Use is made, in particular, ofoxalyl chloride, PCl₅, PCl₃ and thionyl chloride. The reaction can becarried out with or without organic solvent, preferably with addition ofdimethylformamide (DMF) at temperatures of from 0 to 60° C., preferablyfrom 15 to 50° C., particularly preferably from 20 to 30° C. Typicalreaction times are 0.5 to 3, in particular 1 to 2, hours.

[0025] The reaction of the preferably activated carboxylic acid with theamine of the formula (VI) is carried out at basic pH in polar solvents,such as water, alcohols, ketones or ethers, or else in mixtures ofdifferent solvents, in particular in mixtures of water and acetone,water and methanol or water and ethanol. To adjust the desired pH, useis made, in particular, of inorganic bases, such as alkali metalhydroxides or alkoxides, in particular potassium hydroxide or sodiumhydroxide. The reaction is carried out at temperatures of from −10 to40° C., preferably from 0 to 20° C. A typical reaction time is up to 1.5hours, in particular from 0.5 to 1 hour.

[0026] For the reaction according to step (b), a reagent is used whichcan release a species which is capable of forming a cationicintermediate having a double bond, in particular a C—C double bond, andsimultaneously forms a good leaving group. The cationic intermediateformed having the double bond can then be attacked by a nucleophile,preferably intramolecularly, so that a lactone of the formula (VIII) isformed.

[0027] Reagents suitable for such a reaction are in particular thosereleasing halogen cations, preferably N-bromosuccinimide,N-iodosuccinimide or N-chlorosuccinimide. The reaction is preferablycarried out in polar organic solvents, in particular alcohols, such asethanol, methanol or propanol, or else in solvent mixtures with additionof DMF. Here, the pH is above 7. This is preferably achieved by addinginorganic alkali metal salts, in particular hydroxides or alkoxides,such as sodium hydroxide, potassium hydroxide or potassiumtert-butoxide. The reaction is typically carried out at temperatures offrom −10 to 10° C., in particular at below 5° C., for 10 to 24,preferably 12 to 17, hours. The product of the reaction is preferablypurified by crystallization.

[0028] In the context of the invention, it is also envisaged that thereaction according to step (b) is carried out with control of thestereochemistry.

[0029] In the context of the present invention, the radical R¹ can havea structure of the formula (1)

—(CR′R″)_(n)—Z_(m)—Ar  (1),

[0030] in which

[0031] Ar represents a substituted or unsubstituted phenyl radical, asubstituted or unsubstituted 1- or 2-naphthyl radical or a substitutedor unsubstituted heterocyclic ring, which preferably has 5 members andis selected from the group consisting of thiophene, thiazole,isothiazole, pyrrole and particularly preferably pyrazole,

[0032] R′ and R″ represent hydrogen or fluorine or a methyl radical,

[0033] Z represents —P(CR′R″)_(o)— where P is oxygen or sulphur and o isan integer from 0 to 4, in particular 1 or 2,

[0034] m is an integer from 0 to 2, preferably 0 or 1, and

[0035] n is an integer from 2 to 8, in particular an integer from 4 to6.

[0036] The radical R¹ is preferably a radical having 1 to 20 carbonatoms, in particular with halogen substituents, preferably fluorine.Furthermore, R¹ preferably has a structure of the formula (1a)

[0037] in which

[0038] R′ and R″ are hydrogen or fluorine or a methyl radical,

[0039] L′ and L″ independently of one another are hydrogen, halogen, asubstituted or unsubstituted branched or straight-chain alkyl, aryl oralkylaryl group, a substituted or unsubstituted branched orstraight-chain alkoxy or aryloxy group, a substituted or unsubstitutedbranched or straight-chain carboxyalkyl or carboxyaryl group, a nitrogroup or a trifluoromethyl group, and

[0040] Z is —P(CR′R″)_(o)— where P is oxygen or sulphur and o is aninteger from 0 to 4, in particular 1 or 2,

[0041] m is an integer from 0 to 2, preferably 0 or 1, and

[0042] n is an integer from 2 to 8, in particular an integer from 4 to6.

[0043] In particular, L′ or L″ is hydrogen and the respective othersubstituent L′ or L″ represents a halogen atom, preferably chlorine orfluorine, in particular chlorine. In a particularly preferredembodiment, m and o are 1, n is 6 and P is oxygen.

[0044] The radical X⁴ is preferably a halogen atom selected from thegroup consisting of chlorine, bromine and iodine, particular preferenceis given to bromine.

[0045] The radicals R⁴ and R⁵ represent in particular alkyl radicalshaving 1 to 10 carbon atoms, preferably having 1 to 6 carbon atoms,which are preferably unsubstituted or fluorine-substituted. In thecontext of the present invention, R⁴ and R⁵ can also preferably be partof a substituted or unsubstituted cyclic structure R⁴NCR⁵ which may alsocontain a further heteroatom selected from the group consisting of N, Sand O, in particular a five- or six-membered ring.

[0046] The amine of the formula (VI) is in particular a cyclic aminehaving 5 or 6 ring atoms, in particular proline or a derivative thereof.In a particularly preferred embodiment of the invention, the amine ofthe formula (VI) has a stereocentre; particularly preferably, the amineof the formula (VI) is L-proline.

[0047] In a particularly preferred embodiment, the invention relates toa process where the compound of the formula (V) is obtained by reactinga compound of the formula (IV)

[0048] where in the formula (IV) R¹ is a straight-chain or branchedmono-, poly- or unsubstituted alkyl group, a straight-chain or branchedmono-, poly- or unsubstituted alkylene group, a straight-chain orbranched mono-, poly- or unsubstituted aralkyl, alkylaryl or aryl group.

[0049] This is a reaction of the carboxylic acid with a reagent whichresults in a reduction with formation of a C—C double bond. Suitablehere are those reagents which attack only one of the acid functions. Thereaction can be carried out, for example, using formaldehyde, inparticular paraformaldehyde, and an organic base, such as, for example,triethylamine, diisopropylethylamine or piperidine, in particularpiperidine, in organic solvents, such as alcohols, in particularmethanol, ethanol, propanol or mixtures thereof, in particular inisopropanol. The reaction is carried out at temperatures of from 40 to60° C., in particular from 45 to 55° C., until the proportion ofunreacted starting material according to HPLC is below 2%, preferablybelow 1%, particularly preferably below 0.5%.

[0050] In a further embodiment, the invention relates to a process wherethe compound of the formula (IV) is obtained by hydrolysing the compoundof the formula (III)

[0051] in which

[0052] R¹ is a straight-chain or branched mono-, poly- or unsubstitutedalkyl group, a straight-chain or branched mono-, poly- or unsubstitutedalkylene group, a straight-chain or branched mono-, poly- orunsubstituted aralkyl, alkylaryl or aryl group, and

[0053] Y¹ and Y² are identical or different electron-withdrawing groupswhich can be converted into a carboxylic acid.

[0054] According to the invention, the radicals Y¹ and Y² are preferablyselected from the group consisting of CN, carboxylic acid, carboxylicanhydride and carboxylic ester with a C1- to C10-alcohol. In the contextof the present invention, the radicals Y¹ and Y² are in particularradicals of the general structure —CO₂R² and —Co₂R³, where R² and R³represent a mono-, poly- or unsubstituted alkyl radical having 1 to 20,preferably 1 to 10, particularly preferably 1 to 4, carbon atoms, inparticular unsubstituted or fluorine-substituted.

[0055] Suitable for this hydrolysis are all methods known to the personskilled in the art, in particular acidic or basic hydrolysis. In thecontext of the present invention, basic hydrolysis employing alkalimetal hydroxide or alkoxide, in particular sodium hydroxide or potassiumhydroxide, in organic polar solvents, such as alcohols, ketones orethers, in particular cyclic ethers, or in water or in mixtures of twoor more thereof, such as, for example, methanol/water,tetrahydrofuran/water or ethanol/water, if appropriate with the use ofphase-transfer catalysts, is preferred. The reaction is preferablycarried out at temperatures of from 10 to 60° C., in particular from 40to 50° C., particularly preferably at from 20 to 30° C., for 1 to 24, inparticular 1 to 3, hours.

[0056] A further embodiment of the invention comprises a process wherethe compound of the formula (III) is obtained by condensing a compoundof the formula (I) with a compound of the formula (II)

[0057] where

[0058] R¹ is a straight-chain or branched mono-, poly- or unsubstitutedalkyl group, a straight-chain or branched mono-, poly- or unsubstitutedalkylene group, a straight-chain or branched mono-, poly- orunsubstituted aralkyl, alkylaryl or aryl group,

[0059] X¹ is a leaving group,

[0060] Y¹ and Y² are identical or different electron-withdrawing groupswhich can be converted into a carboxylic acid.

[0061] In the context of the invention, the substituent X¹ is preferablya halogen atom, a tosylate group or a triflate group, in particularchlorine or bromine.

[0062] The condensation reaction is carried out in the presence of acompound capable of deprotonating a compound of the formula (II).According to the invention, use is made, in particular, of inorganicbases, such as alkali metal alkoxides or carbonates, preferablypotassium carbonate or sodium ethoxide. The reaction is carried out inpolar solvents, such as, for example, alcohols, ketones or ethers,preferably with addition of DMF, at temperatures of from 90 to 150° C.,in particular from 110 to 130° C., for 10 to 20, preferably 12 to 18,hours.

[0063] In addition, a preferred embodiment of the invention relates to aprocess where the compound R¹-X¹ is obtained by reacting astraight-chain or branched mono- or polysubstituted alkane having twoleaving groups X¹ and X² with a mono-, poly- or unsubstituted benzenederivative, preferably a phenol derivative.

[0064] This reaction is carried out under conditions permitting areaction of the benzene derivative, in particular the phenol, in thesense of a substitution reaction, preferably under basic conditions. Thebasic conditions can be set, for example, by adding a hydroxide, analkoxide or a carbonate, in particular by adding sodium carbonate orpotassium carbonate. The alkane used is preferably simultaneously usedas solvent, if appropriate with addition of DMF. In the context of theinvention, the reaction is carried out at temperatures of from 100 to130° C., in particular at from 115 to 125° C., for 2 to 8, preferably 3to 6, hours.

[0065] In the context of the invention, preference is given to alkaneshaving a general structure X¹—(CR′R″)_(n)—Z_(m)—X² where

[0066] R′ and R″ represent hydrogen or fluorine,

[0067] Z represents —P(CR′R″)_(o)— where P is oxygen or sulphur and o isan integer from 0 to 4, in particular 1 or 2,

[0068] X¹ and X² are good leaving groups, preferably independently ofone another selected from the group consisting of halogen, triflate andtosylate, in particular chlorine or bromine,

[0069] m is an integer from 0 to 1, preferably 0, and

[0070] n is an integer from 2 to 8, in particular an integer from 4 to6.

[0071] In the context of the invention, it is possible, in particular,that X¹ and X² are identical. In this case, in the substitution reactionno product mixtures difficult to separate are formed. In the context ofthe invention, the alkane is in particular employed in excess. Theunreacted alkane can be recovered.

[0072] In one possible embodiment of the present invention, the startingmaterial used can be epsilon-caprolactone, a cheap starting materialwith low toxicity. Epsilon-caprolactone can be converted into various1,6-bifunctional structures with 6 carbon atoms. Such bifunctionalstructures have two different substituents, allowing selectivetransformation of one of the two ends.

[0073] There are a number of options for opening the ring of theepsilon-caprolactone. The ring opening can be carried out by amidationusing, for example, benzylamine (solvent, for example: toluene,tetrahydrofuran or xylene), ethanolamine (preferably without additionalsolvent, since ethanolamine for its part acts as a solvent),dibutylamine or isopropylbenzylamine, or else by esterification ornucleophilic ring opening, preferably using hydrogen bromide, whichresults in the formation of 6-bromohexanoic acid.

[0074] Advantageously, 6-bromohexanoic acid is formed by distillingepsilon-caprolactone in, for example, 48% strength hydrobromic acid, forabout 3-4 hours. The reaction mixture is then diluted and mixed, forexample, with toluene, and the acidic phase is then separated off. Lastacid residues can be removed, for example, by azeotropic distillation.After the end of distillation, a two-fold excess of alcohol, for examplemethanol, ethanol or n-propanol, is added, and the excess alcohol isremoved again by distillation.

[0075] In the context of the present invention, it is possible to useboth the bromoesters obtained in this manner, and the free acids.

[0076] The benzene derivative is preferably a phenol derivative, inparticular a phenol having one or two further substituents on thearomatic ring. Preferred substituents are, for example, halogen, analkyl or alkoxy group, a nitro group or a trifluoromethyl group, inparticular chlorine.

[0077] In the context of the invention, it is also possible to use thecompound of the formula (VIII) in a reaction where a compound of theformula (IX) is formed

[0078] in which

[0079] R¹ is a straight-chain or branched mono-, poly- or unsubstitutedalkyl group, a straight-chain or branched mono-, poly- or unsubstitutedalkylene group, a straight-chain or branched mono-, poly- orunsubstituted aralkyl, alkylaryl or aryl group,

[0080] X⁴ is a functional group capable of forming a cationicintermediate in a reaction with a C—C double bond and is a good leavinggroup, and

[0081] R⁶ is selected from the group consisting of OH, O⁻M⁺, O⁻M²⁺,where M is an alkali metal, an alkaline earth metal or an earth metal ora cation of an organic nitrogen base, and OR, where R is a substitutedor unsubstituted alkyl or alkylene radical having 1 to 15 carbon atoms.

[0082] In the context of the present invention, R⁶ is preferablyselected from the group consisting of OH, O⁻Na⁺, O⁻K⁺, OR, where R is anunsubstituted alkyl radical having 1 to 10 carbon atoms.

[0083] The compound of the formula (IX) can be obtained, for example, byhydrolysis. In principle, all methods known to the person skilled in theart are suitable. Particular preference is given to acid hydrolysis withaddition of mineral acids, such as, for example, hydrochloric acid orsulphuric acid. According to the invention, the reaction is carried outin polar solvents, such as water or alcohols, in particular water, attemperatures above 80° C., preferably at 100° C., for at least 24 hours,preferably for at least 36 hours, particularly preferably for at least48 hours.

[0084] Moreover, in the context of the present invention, it is possibleto use the compound of the formula (IX) in a reaction where an oxiraneof the formula (X)

[0085] is obtained in which

[0086] R¹ is a straight-chain or branched mono-, poly- or unsubstitutedalkyl group, a straight-chain or branched mono-, poly- or unsubstitutedalkylene group, a straight-chain or branched mono-, poly- orunsubstituted aralkyl, alkylaryl or aryl group, and

[0087] R⁶ is selected from the group consisting of OH, O⁻M⁺, O⁻M²⁺,where M is an alkali metal, an alkaline earth metal or an earth metal ora cation of an organic nitrogen base, and OR, where R is a substitutedor unsubstituted alkyl or alkylene radical having 1 to 15 carbon atoms.

[0088] The reaction for forming the oxirane takes place under conditionswhich permit the intramolecular attack of the OH group in the sense of asubstitution reaction. According to the invention, the reaction iscarried out in a basic medium, a suitable pH being established, forexample, by addition of hydroxide or alkoxide, in particular by additionof potassium tert-butoxide. The reaction can take place in polarsolvents, such as water, alcohols, ketones, ethers, preferably MTBE, orelse in mixtures of two or more of these solvents. Particular preferenceis also given to carrying out the reaction in a dried and concentratedsolution of a nonpolar solvent, such as toluene from the previousreaction step (see Example 5). In the context of the invention, thereaction is carried out at temperatures of from −10 to 10° C., inparticular temperatures below 5° C., for 0.5 to 2.5, preferably 1 to 2,hours. Whether the reaction has gone to completion can be checked, forexample, by HPLC.

[0089] However, in the context of the present invention it is alsopossible that, after cyclization, for example, a salt of anoxiranecarboxylic acid is present which is then converted in a furtherreaction step into a carboxylic ester, in particular an ester with analcohol having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms,particularly preferably 1 to 6 carbon atoms. Suitable reactionconditions for the esterification are described, for example, in“Organikum”, 18^(th) edition, 1990, Deutscher Verlag der Wissenschaften,Berlin, 400-408.

[0090] The invention relates in particular to a process which can bedescribed by the following scheme, where the radicals R¹, R⁴, R⁵, R⁶,X¹, X², X⁴, Y¹ and Y² are as defined above. R represents H or asubstituted or unsubstituted alkyl or alkylene radical having 1 to 15carbon atoms. X³ is preferably a radical which corresponds to thedefinition of L′, particularly preferably a halogen, in particularchlorine:

[0091] In the embodiment described above, an oxiranecarboxylic acid or aderivative thereof is obtained in eight synthesis steps from readilyavailable starting materials. The last reaction step is the cyclization,so that it is not necessary to carry out further reaction steps with thereactive oxirane.

[0092] The invention also provides a process for preparingoxiranecarboxylic acids and derivatives thereof, comprising thesynthesis of a compound of the formula (IX), comprising the conversionof a compound of the formula (VIII) into the compound of the formula(IX)

[0093] where

[0094] R¹ is a straight-chain or branched mono-, poly- or unsubstitutedalkyl group, a straight-chain or branched mono-, poly- or unsubstitutedalkylene group, a straight-chain or branched mono-, poly- orunsubstituted aralkyl, alkylaryl or aryl group,

[0095] the radicals R⁴ and R⁵ are identical or different straight-chainor branched mono-, poly- or unsubstituted alkyl groups, straight-chainor branched mono-, poly- or unsubstituted alkylene groups,straight-chain or branched mono-, poly- or unsubstituted aralkyl,alkylaryl or aryl groups, where R⁴NCR⁵ may be part of a substituted orunsubstituted cyclic structure which may also contain a furtherheteroatom selected from the group consisting of N, S and O,

[0096] X⁴ is a functional group capable of forming a cationicintermediate in a reaction with a C—C double bond and is a good leavinggroup, and

[0097] R¹ and R⁴NCR⁵ are not simultaneously —(CH₂)₆—OBn and anunsubstituted five-membered ring, respectively, and

[0098] R⁶ is selected from the group consisting of OH, O⁻M⁺, O⁻M²⁺,where M is an alkali metal, an alkaline earth metal or an earth metal ora cation of an organic nitrogen base, and OR, where R is a substitutedor unsubstituted alkyl or alkylene radical having 1 to 15 carbon atoms.

[0099] Further reaction steps of this process may, in particular, be thesteps described in more detail above.

[0100] In addition, the invention also relates to a process forpreparing oxiranecarboxylic acids and derivatives thereof, comprisingthe synthesis of a compound of the formula (X), comprising a reaction ofa compound of the formula (IX) in which an oxirane of the formula (X) isformed

[0101] where

[0102] R¹ is a straight-chain or branched mono-, poly- or unsubstitutedalkyl group, a straight-chain or branched mono-, poly- or unsubstitutedalkylene group, a straight-chain or branched mono-, poly- orunsubstituted aralkyl, alkylaryl or aryl group,

[0103] R¹ is not —(CH₂)₆—OH,

[0104] X⁴ is a functional group capable of forming a cationicintermediate in a reaction with a C—C double bond and is a good leavinggroup, and

[0105] R⁶ is selected from the group consisting of OH, O⁻M⁺, O⁻M²⁺,where M is an alkali metal, an alkaline earth metal or an earth metal ora cation of an organic nitrogen base, and OR, where R is a substitutedor unsubstituted alkyl or alkylene radical having 1 to 15 carbon atoms.

[0106] Further embodiments of this process may comprise the reactionsteps described in more detail above.

[0107] In the context of the present invention, it is also possible thata process according to the invention takes place with stereochemicalcontrol of the individual reaction steps.

[0108] The compounds prepared according to the invention may contain acentre of chirality. Accordingly, the invention embraces both theracemates and the enantiomers and their mixtures. For racemateseparation, methods known to the person skilled in the art are employed.If the process takes place under stereochemical control, it is possibleto prepare the (+)-enantiomers of the compounds, for example by usingchiral auxiliaries. The chiral auxiliaries used are, in particular,chiral amino acids; for example, the compound (VI) used can beL-proline, in particular. However, in the context of the presentinvention it is also possible to prepare the (−)-enantiomers.

[0109] In a preferred embodiment, the present invention relates to aprocess for preparing etomoxir, palmoxirate or clomoxir, in particular(+)-etomoxir.

[0110] The invention furthermore also provides the compounds prepared bya process according to the invention, in particular theoxiranecarboxylic acids and derivatives thereof, which can be preparedby the processes according to the invention. In addition, the inventionalso relates to compounds of the formula (VII), preparable by step (a)of a process according to the invention.

[0111] The invention furthermore relates to the use of anoxiranecarboxylic acid prepared according to the invention or aderivative thereof in pharmaceutical compositions, in particular to theuse of the oxiranecarboxylic acids prepared according to the inventionand derivatives thereof for treating disorders associated with glucosemetabolism, lipid metabolism, cardiovascular disorders and cardiacinsufficiency. Specifically, these are, for example, diabetes,hyperlipaemia, coronary heart disease such as angina pectoris ormyocardial infarction, states after myocardial infarction or dilatativecardiomyopathies.

[0112] Below, the invention is illustrated in more detail by exemplarysyntheses.

EXAMPLES Example 1

[0113] 1. Formation of R¹-X¹: 6-(4-chlorophenoxy)hexyl chloride (6-CPHC)in 1,6-dichlorohexane

[0114] Substances used: 4-Chlorophenol 31.5 kg   1 eq. 245 mol1,6-DiChlorohexane 280 l 7.9 eq. 1.93 kmol Potassium carbonate 44 kg 1.3eq. 318 mol DMF (dimethylformamide) 75 kg n-Heptane 200 kg Water 390 l

[0115] 4-Chlorophenol (as a melt) was added to 1,6-dichlorohexane,followed by DMF. Potassium carbonate was added to the mixture. Theresulting viscous mixture was heated at about 120° C. The reaction wascontinued for 3-6 hours until HPLC showed that the proportion of4-chlorophenol was below 1 area %.

[0116] Once the reaction had been deemed to be complete, the reactionmixture was cooled to about 60° C. The solid was filtered off. Thefilter cake was washed with DMF (about 20 l).

[0117] Potassium carbonate (15 kg), n-heptane (200 kg) and water (235 1)were added to the combined mother liquor and washing solution. Thetemperature of the resulting two-phase mixture was adjusted to 60° C.,and the aqueous phase was removed. The organic phase was washed withwater (155 l) at about 60° C.

[0118] The organic phase that remained was concentrated under reducedpressure at about 100° C. Once stirring was no longer possible owing tothe viscosity of the reaction product, the liquid was used for the nextreaction step.

[0119] 2. Condensation Reaction: Synthesis of Diethyl6-(4-chlorophenoxy)hexylmalonate (6-CPHMA-DEE) in Methanol

[0120] Substances used: 6-CPHC in 1,6-diChlorohexane ½ of the batch fromthe previous synthesis step Diethyl malonate 28 l 1.5 eq. 186 molPotassium carbonate 35 kg 2.1 eq. 253 mol Potassium bromide 17 kg 1.2eq. 143 mol Methanol 80 l DMF 75 kg 36% strength hydrochloric acid 5 ln-Heptane 135 kg Water 225 l

[0121] Half of the 6-CPHC reaction batch in 1,6-dichlorohexane wasdistilled under reduced pressure (<10 mbar). The boiling point waspreferably kept below 130° C. The distillate was analysed for1,6-dichlorohexane content and could be used for a further reactionaccording to step 1.

[0122] The residue was analysed for 1,6-dichlorohexane. The distillationwas stopped once the content according to gas chromatography was below20 area %.

[0123] After the end of the distillation, the residue was diluted withDMF and transferred to another reactor. Diethyl malonate, potassiumcarbonate and potassium bromide were added to the DMF solution. Theresulting viscous mixture was heated to about 130° C. The reactionmixture was kept at 130° C. for 12-18 hours until the content ofstarting material according to HPLC was below 1 area %.

[0124] The reaction mixture was cooled to 60° C. and the solid wasfiltered off. The filter cake, which had been sucked dry, was washedwith DMF (30 1). n-Heptane (135 kg) and water (150 1) were added to themother liquor. The mixture was warmed to about 40° C. Using 36% strengthhydrochloric acid (about 5 1), the pH was adjusted to pH=2. The aqueousphase was removed and the organic phase was washed with water (75 1).

[0125] Following analysis, two reaction batches could be combined. Thecombined reaction batches were concentrated at a temperature of at most100° C. When the concentration came to an end, the pressure was reducedto remove as much as possible of the remaining diethyl malonate.

[0126] Methanol (80 1) was added to the residue to obtain aconcentration suitable for the next reaction.

[0127] 3. Hydrolysis and Formation of the Double Bond:8-(4-chlorophenoxy)-2-methyleneoctanoic acid (8-CPMOA)

[0128] Substances used: 6-CPHMA-DEE in methanol Two combined batchesfrom step 2 Sodium hydroxide, 50% strength 114 kg 6 eq. 1.44 molsolution Methanol 280 l Water 1030 l n-Heptane 675 kg MTBE (methyltert-butyl ether) 280 l 36% strength hydrochloric acid 163 l Isopropanol440 l Paraformaldehyde 12.5 kg Piperidine 29 l

[0129] The sodium hydroxide solution was added to the water/methanolmixture. The temperature of the resulting mixture was adjusted to 50° C.6-CPHMA-DEE in methanol was added to this mixture. The addition rate wasadjusted such that the temperature remained below 52° C. The additionwas carried out as quickly as possible. After the addition had ended,water (140 l) was added. Following the addition of water, the reactionwas deemed to have been completed. Small amounts of the startingmaterials could be removed later on in the process.

[0130] Methanol was removed under reduced pressure at at most 50° C.During the concentration, water (190 l) was added to ensure that theintermediate remained soluble. n-Heptane (210 kg) and water (100 l) wereadded, and the mixture was heated to 75° C. The aqueous phase, whichcontained the product, was removed and transferred into another reactor.

[0131] The temperature of the aqueous phase was lowered to below 50° C.,and MTBE (280 l) was then added. 36% strength hydrochloric acid (about130 l) was added to this mixture to adjust the pH to about 1. During theaddition of the hydrochloric acid, the temperature was kept below 40° C.The aqueous phase was separated from the organic phase, which was washedwith water (190 l) at 40° C.

[0132] Isopropanol (290 l) was added to the organic phase. Under reducedpressure, MTBE was removed at at most 40° C. The distillation wascontinued until the volume which remained in the reactor was about 225l.

[0133] Further isopropanol (150 l) and paraformaldehyde (12.5 kg) wereadded to the resulting isopropanol solution. The resulting mixture waswarmed to about 50° C. To this mixture, piperidine (29 l) was added asquickly as possible, without the temperature exceeding 52° C. Thisexothermal reaction resulted in a highly viscous reaction mixture.

[0134] The reaction was monitored by process-tracking HPLC analysis.Once, after 1-2 hours, less than 10% of free dicarboxylic acid waspresent, the mixture was heated at reflux. This was continued until,according to HPLC, only negligible amounts (<2%) of the intermediatewere present. During the reaction, carbon dioxide was released. Atypical reaction time was 3 hours. During the reaction, the viscosity ofthe reaction mixture was reduced, and towards the end, an almost clearsolution was present.

[0135] The reaction was deemed to have ended once less than 5 area %(HPLC) of the intermediate was present. By concentration underatmospheric pressure, the volume in the reactor was reduced to about 160l. Water (270 l) and n-heptane (445 kg) were added to the residue. 36%strength hydrochloric acid (about 33 l) was added until a pH of 1 hadbeen reached. The resulting two-phase system was heated to at least 70°C. The aqueous phase was removed from the organic phase, which waswashed with water (140 l) at at least 70° C.

[0136] The volume of the organic phase was reduced under reducedpressure and at at most 50° C. The distillation was continued untilabout 490 l remained in the reactor. Towards the end of thedistillation, a temperature of 30° C. was maintained in the reactor.After complete concentration, an 8-CPMOA seed crystal was added.

[0137] The reactor content was carefully cooled to 0C.

[0138] The product was isolated by filtration. The filter cake waswashed with cold n-heptane (20 kg).

[0139] Following filtration, the product could be used directly for thenext reaction, without further drying. Each reaction batch gave about37-40 kg of 8-CPMOA.

[0140] 4. Amide Formation: 8-CPMOA-Proline

[0141] Substances used: 8-CPMOA 40 kg (dry 141 mol weight) Sodiumhydroxide, 50% strength 24 l 3.00 eq. 423 mol solution L-proline 21 kg1.30 eq. 182 mol Water 85 l Ethyl acetate 85 kg Thionyl chloride 14 l1.40 eq. 198 mol Acetone 38 kg DMF 106 kg MTBE 154 kg 36% strengthhydrochloric acid 25 l Sodium chloride 25 kg Water 76 l

[0142] The 8-CPMOA (about 40 kg dry weight) obtained by filtration wasadded to ethyl acetate (85 kg). From the resulting solution, about 19 1of liquid were evaporated under reduced pressure at at most 40° C. DMF(1 l) was added, and the temperature in the reactor was adjusted to 45°C.

[0143] Thionyl chloride (14 l) was added over a period of 60 min. Afterthe end of the addition, the reaction was continued until HPLC showedthat all starting material had been consumed. A typical reaction timeafter the end of the addition was 1-2 hours.

[0144] By distillation at at most 45° C., the ethyl acetate and theexcess thionyl chloride were removed. Acetone (38 kg) was added, and theresulting mixture was stirred for at least 20 min to obtain completedissolution.

[0145] Sodium hydroxide solution (24 l) and L-proline (21 kg) were addedto water (85 l). During the addition of the L-proline, the temperaturewas kept below 20° C. The solution of the acid chloride and acetone wasadded to this mixture, the temperature being kept below 20° C. After theend of the addition, the reaction was continued until HPLC showed thatall acid chloride had been consumed. A normal reaction time was lessthan 30 min.

[0146] The acetone was evaporated under reduced pressure at at most 40°C. In total, 48 1 of liquid were evaporated. MTBE (70 kg) was added, andthe resulting two-phase system was warmed to about 40° C. The aqueousphase (which contained product) was removed. Further MTBE (84 kg) wasadded to the aqueous phase, and the aqueous phase was acidified with 36%strength hydrochloric acid (about 25 l). The pH of the solution wasadjusted to a value of 1-2. The temperature of the reactor contents wasadjusted to 40° C., and the aqueous phase was removed. The organic phasewas washed with a mixture of water (76 l) and sodium chloride (25 kg),at about 40° C.

[0147] The MTBE was removed by distillation at at most 40° C. Once theresidue had an oily consistency, DMF (105 kg) was added, so that thesolution could be used for the next reaction step.

[0148] 5. Lactone Formation: 8-CPMOA-Lactone

[0149] Substances used: 8-CPMOA-proline in DMF 1 batch from the previousreaction step N-Bromosuccinimide (NBS) 40 kg 2.05 eq. 289 mol Potassiumtert-butoxide 16 kg 1.01 eq. 143 mol Water 1350 l Sodium thiosulphate 30kg Sodium carbonate 17 kg DMF 177 kg Ethanol 400 l MTBE 570 l Methanol510 l

[0150] A solution of NBS (50 kg) and DMF (120 kg) was prepared. Todissolve almost all of the NBS, it was necessary for the DMF to be atroom temperature.

[0151] Potassium tert-butoxide was added at a temperature of below 50Cto the solution of 8-CPMOA-proline in DMF from the previous reactionstep. After the end of the addition, the pH of the solution was above 7;if this was not the case, more potassium tert-butoxide was added.

[0152] The solution of NBS was added to the solution of 8-CPMOA-prolineat such a rate, that the temperature did not exceed 0° C. A typicaladdition time was 1-2 hours. After the end of the addition, thetemperature was increased to 2° C. and maintained at this value for 1hour. The temperature was increased to 5° C. The mixture was kept atthis reaction temperature for about 12-17 hours. During the reaction, awhitish solid was formed.

[0153] After the end of the reaction, the reaction solution was cooledto 0° C. The precipitated solid was removed by centrifugation. Thecentrifugation cake was washed with DMF (57 kg). To obtain all of theproducts, a fine filtration was carried out. Strict attention was paidto exact temperature control of the mother liquor at a value below 5° C.Owing to its low thermal stability, the solid was immediately suspendedin sufficient water.

[0154] Water (230 l) and MTBE (570 l) were added to the mother liquor.The addition of water was exothermic, which required the temperature tobe kept below 5° C. A solution of sodium thiosulphate (30 kg) in water(120 l) was added. This addition, too, was exothermic. The sodiumthiosulphate destroyed the remaining NBS, so that temperature controlwas no longer required.

[0155] The resulting two-phase system was stirred for at least 30 min.The lower phase was then removed. Water (490 l) and sodium carbonate (17kg) were added, and the reaction mixture was warmed to 40° C. Theaqueous phase was removed. The organic phase was washed with water (510l).

[0156] The organic phase was concentrated under atmospheric pressureuntil about 170 1 remained. Methanol (510 l) was added, and theevaporation was continued until the boiling point exceeded 63° C., i.e.until all MTBE had evaporated. By further concentration, the volume inthe reactor was adjusted to about 170 1. The product was crystallized bycarefully cooling the solution. At about 30° C., the solution was seededto initiate crystallization. Large amounts of seed crystals wererequired.

[0157] To ensure enantiomeric purity of the end product, arecrystallization was carried out.

[0158] Recrystallization of 8-CPMOA-lactone

[0159] About 50 kg (dry weight) of 8-CPMOA-lactone (this corresponded toabout 1½ batches) were added to ethanol (350 l). By distillation underatmospheric pressure, about 100 l of liquid were evaporated. Thesolution was cooled to 45° C., so that the solution could be seeded.Here, too, large amounts of seed crystals were required to achievecrystallization. The temperature was lowered slowly to about 15-18° C.

[0160] The product was isolated by slow filtration and washed withethanol. Following filtration, the product was initially dried at roomtemperature for a number of hours. The temperature was then increased to40° C. The yield achieved here was 42 kg per recrystallization, whichcorresponded to about 28 kg per synthesis batch.

[0161] 6. Release of the Carboxylic Acid:2-bromoethyl-2-hydroxy-8-(4-chlorophenoxy)octanoic acid (BH-COA)

[0162] Substances used: 8-CPMOA-lactone 42 kg  92 mol Toluene 290 lWater 450 l n-Heptane 20 l 36% strength hydrochloric acid 700 l 92 eq.8400 mol

[0163] 8-CPMOA-lactone (42 kg) was added to water (180 l). 36% strengthhydrochloric acid (700 l) was added to the suspension.

[0164] The mixture was heated at reflux. The reaction was kept at refluxtemperature for at least 24 hours and up to 48 hours. Since bothstarting materials were present as oils, the mixture had to be stirredvigorously.

[0165] After the reaction had ended, the reaction mixture was cooled to75° C. and toluene (270 l) was added. The aqueous phase was removed andthe toluene phase was washed with water (270 l) at 75° C.

[0166] At a temperature of below 60° C., toluene was removed bydistillation until a volume of about 200 1 remained. The solution wascooled to about 40-45° C., so that a seed crystal could be added. Oncethe crystallization had started, the reaction mixture was warmed toabout 55° C. and then crystallized by cooling. Cooling was continued upto a temperature of 15° C.

[0167] The product was isolated by filtration and then washed withtoluene (20 l). The filter cake was washed with n-heptane (20 l).

[0168] The crude product could be used without drying for the nextreaction step. A typical yield was about 24 kg of BH-COA as calculateddry weight.

[0169] 7. Synthesis of Etomoxir (Potassium Salt)

[0170] Substances used: BH-COA 16 kg (dry 42 mol weight) Potassiumtert-butoxide 10 kg 2.11 eq. 89 mol Water Methanol 160 l MTBE 315 kgPotassium hydroxide 3 kg Water 160 l

[0171] BH-COA (16 kg as dry weight) were added to MTBE (160 kg). Theresulting solution was cooled to about 0-5° C. Potassium tert-butoxidewas added to this mixture at a rate such that the temperature remainedbelow 5° C. A typical addition time was about 60 min.

[0172] After the addition had ended, the reaction was continued (about30-60 min) until HPLC showed that all of the starting materials hadreacted.

[0173] After the end of the reaction, water (160 l) was added. Theaqueous phase (which contained the product) was removed. MTBE (155 kg)was added to the aqueous phase, and the pH was adjusted with 36%strength hydrochloric acid to a value of 1-2. The temperature of thesystem was kept at about 40° C.

[0174] The aqueous phase was removed and the organic phase was washedwith water (160 l) at about 40° C.

[0175] MTBE was removed by distillation under reduced pressure at about40° C. until a volume of about 100 1 remained. Methanol (120 l) wasadded and the distillation was continued until the residual volume wasabout 60 1.

[0176] A solution of potassium hydroxide (3 kg) and methanol (30 l) wasadded to the methanolic solution. During the addition, the productprecipitated as potassium salt. After the end of the addition, theviscous mixture was cooled to about 0° C.

[0177] The product was isolated by centrifugation and then washed withmethanol (10 l). The product obtained by centrifugation was dried at 35°C. A typical dry yield was about 12 kg.

[0178] 8. Esterification: Synthesis of (+)-Etomoxir

[0179] Substances used: Etomoxir, potassium salt 3.5 kg 10.4 mol Ethylbromide 1.7 kg 1.50 eq. 15.6 mol n-Heptane 39 l Water 44 l Sodiumcarbonate 1.2 kg DMF 16 l Ethanol 400 l

[0180] Ethyl bromide (1.7 kg) was added to DMF (14 l). The mixture waswarmed to 38° C. Etomoxir potassium salt was added to the mixture at arate such that no lumps were formed.

[0181] The reaction was continued at 40° C. for about 18-20 hours untilHPLC showed that the starting materials had been consumed. During thereaction time, the reaction mixture became less and less viscous, and atthe end of the reaction, only a small precipitate of potassium bromidewas present.

[0182] The precipitate was removed by filtration and the filter cake waswashed with DMF (2 l). n-Heptane (14 l) and water (14 l) were added tothe mother solution. The two-phase system was heated to 50° C. and theaqueous phase was removed. n-Heptane (10 l) was added to the organicphase. The organic phase was washed at 50° C. first with water (15 l)and sodium carbonate (1.2 kg) and then with water (15 l).

[0183] 10 l of n-heptane were distilled off under reduced pressure at atmost 50° C. The product mixture was filtered off with suction through afine filter. The fine filter was then rinsed with n-heptane (10 l).

[0184] From the filtered solution, 14 1 of n-heptane were distilled offunder reduced pressure at at most 50° C. The solution was cooled toabout 19-20° C. so that seeding could be carried out. To prevent theformation of an oil, the mixture was stirred at high speed during thecrystallization. After seeding of the solution, the solution was cooledvery carefully to about −5° C.

[0185] The product was isolated by filtration and washed with 5 l ofn-heptane at a temperature of below 0° C. The product was carefullysucked dry, since (+)-etomoxir melts at about 35° C. and had to betreated very carefully.

[0186] The product was dried under reduced pressure at at most 20° C. Atypical yield was 2.4 kg of (+)-etomoxir.

Example 2

[0187] The general synthesis of the oxiranecarboxylic acids correspondedto that of Example 1 described above. However, in the first reactionstep, the amount of 1,6-dichlorohexane was reduced from 7.9 to 3equivalents to increase the yield of the reaction process and to reducethe raw material costs. This modification did result in an increasedformation of the byproduct 1,6-bis-(4-chlorophenyl)hexane; however, thiswas easily removed in step 3. For further processing, water was added tothe reaction mixture and the product was extracted with MTBE. In thisway, the filtration originally required became redundant.

Example 3

[0188] In this example, too, the general synthesis of theoxiranecarboxylic acids corresponded to the reaction scheme described inExample 1, if appropriate with the modification according to Example 2.However, instead of potassium carbonate, sodium ethoxide was used asstarting material for the reaction. The result of this modification wasthat the reaction had finished after only 3-4 hours and not as beforeafter 18 hours. Moreover, the reaction required a lower temperature andhad the advantage that fewer byproducts were formed.

Example 4

[0189] In this example, too, the general synthesis of theoxiranecarboxylic acids corresponded to the reaction scheme described inExample 1, if appropriate with the modification according to Example 2.Instead of potassium carbonate, sodium ethoxide was, according toExample 3, used as starting material for the reaction. In the lactoneformation according to step 5, the end product was purified byrecrystallization from a mixture of isopropanol and heptane; furtherrecrystallization was not required.

[0190] For the final release of the carboxylic acid according to step 6,50% strength sulphuric acid was used instead of hydrochloric acid.

Example 5

[0191] In this example, too, the general synthesis of theoxiranecarboxylic acids corresponded to the reaction scheme described inExample 1, if appropriate with the modifications according to Examples2, 3 and/or 4. However, 8-CPMOA-lactone was heated by heating at125-130° C. in a mixture of water and sulphuric acid for 8-12 hours. Theproduct was isolated analogously to the process described; however, thetoluene solution was, after drying and concentration by azeotropicdistillation, used for the next step without further processing. Bythis, it was possible to prevent the formation of chlorinatedbyproducts, which resulted in an increased yield, a shorter reactiontime and a simplified process.

[0192] The solution thus obtained was then treated with potassiumtert-butoxide. The reaction product was worked up analogously to theprocess described; however, instead of hydrochloric acid, dilutephosphoric acid was used. For precipitating the product, the solventused was n-propanol and instead of potassium hydroxide and methanol, anaqueous solution of potassium carbonate was used. The solution of thepotassium salt of the reaction product in n-propanol was then heateduntil an almost clear solution was obtained. The product was collectedby filtration at or below room temperature and then dried. Subsequently,the product was recrystallized from ethanol. These modifications of thelast process step resulted in improved filtration properties of thematerial, which in the end also led to an increased quality of theproduct.

1. Process for preparing oxiranecarboxylic acids and derivativesthereof, comprising the synthesis of a compound of the formula (VIII)

in which R¹ is a straight-chain or branched mono-, poly- orunsubstituted alkyl group, a straight-chain or branched mono-, poly- orunsubstituted alkylene group, a straight-chain or branched mono-, poly-or unsubstituted aralkyl, alkylaryl or aryl group, the radicals R⁴ andR⁵ are identical or different straight-chain or branched mono-, poly- orunsubstituted alkyl groups, straight-chain or branched mono-, poly- orunsubstituted alkylene groups, straight-chain or branched mono-, poly-or unsubstituted aralkyl, alkylaryl or aryl groups, where R⁴NCR⁵ may bepart of a substituted or unsubstituted cyclic structure which may alsocontain a further heteroatom selected from the group consisting of N, Sand O, X⁴ is a functional group capable of forming a cationicintermediate in a reaction with a C—C double bond and is a good leavinggroup, and R¹ and R⁴NCR⁵ are not simultaneously —(CH₂)₆—OBn and anunsubstituted five-membered ring, respectively, comprising the steps (a)of reacting a compound of the formula (V) with an amine of the formula(VI) to give a compound of the formula (VII)

in which the radicals R¹, R⁴ and R⁵ are as defined above; and (b)converting a compound of the formula (VII) into a lactone of the formula(VIII).
 2. Process according to claim 1, characterized in that thecompound of the formula (V) is obtained by reacting a compound of theformula (IV)

where in the formula (IV) R¹ is a straight-chain or branched mono-,poly- or unsubstituted alkyl group, a straight-chain or branched mono-,poly- or unsubstituted alkylene group, a straight-chain or branchedmono-, poly- or unsubstituted aralkyl, alkylaryl or aryl group. 3.Process according to claim 2, characterized in that the compound of theformula (IV) is obtained by hydrolysing the compound of the formula(III)

in which R¹ is a straight-chain or branched mono-, poly- orunsubstituted alkyl group, a straight-chain or branched mono-, poly- orunsubstituted alkylene group, a straight-chain or branched mono-, poly-or unsubstituted aralkyl, alkylaryl or aryl group, and Y¹ and Y² areidentical or different electron-withdrawing groups which can beconverted into a carboxylic acid.
 4. Process according to claim 3,characterized in that the compound of the formula (III) is obtained bycondensing a compound of the formula (I) with a compound of the formula(II)

where R¹ is a straight-chain or branched mono-, poly- or unsubstitutedalkyl group, a straight-chain or branched mono-, poly- or unsubstitutedalkylene group, a straight-chain or branched mono-, poly- orunsubstituted aralkyl, alkylaryl or aryl group, X¹ is a leaving group,Y¹ and Y² are identical or different electron-withdrawing groups whichcan be converted into a carboxylic acid.
 5. Process according to claim4, characterized in that the compound R¹-X¹ of the formula (I) isobtained by reacting a straight-chain or branched mono- orpolysubstituted alkane having two leaving groups X¹ and X² with a mono-,poly- or unsubstituted benzene derivative.
 6. Process according to anyof claims 1 to 5, characterized in that the compound of the formula(VIII) is employed in a reaction where a compound of the formula (IX) isformed

in which R¹ is a straight-chain or branched mono-, poly- orunsubstituted alkyl group, a straight-chain or branched mono-, poly- orunsubstituted alkylene group, a straight-chain or branched mono-, poly-or unsubstituted aralkyl, alkylaryl or aryl group, X⁴ is a functionalgroup capable of forming a cationic intermediate in a reaction with aC—C double bond and is a good leaving group, and R⁶ is selected from thegroup consisting of OH, O⁻M⁺, O⁻M²⁺, where M is an alkali metal, analkaline earth metal or an earth metal or a cation of an organicnitrogen base, and OR, where R is a substituted or unsubstituted alkylor alkylene radical having 1 to 15 carbon atoms.
 7. Process according toclaim 6, characterized in that the compound of the formula (IX) isemployed in a reaction where an oxirane of the formula (X)

is obtained in which R¹ is a straight-chain or branched mono-, poly- orunsubstituted alkyl group, a straight-chain or branched mono-, poly- orunsubstituted alkylene group, a straight-chain or branched mono-, poly-or unsubstituted aralkyl, alkylaryl or aryl group, and R⁶ is selectedfrom the group consisting of OH, O⁻M⁺, O⁻M²⁺, where M is an alkalimetal, an alkaline earth metal or an earth metal or a cation of anorganic nitrogen base, and OR, where R is a substituted or unsubstitutedalkyl or alkylene radical having 1 to 15 carbon atoms.
 8. Processaccording to any of claims 1 to 7, characterized in that thesubstituents are, independently of one another, defined as follows: R¹is a radical having 1 to 20 carbon atoms, in particular with halogensubstituents, preferably fluorine, the radicals R⁴ and R⁵ are part of asubstituted or unsubstituted cyclic structure R⁴NCR⁵ which may alsocontain a further heteroatom selected from the group consisting of N, Sand O, in particular of a five- or six-membered ring, X¹ is a halogenatom, a tosylate group, a triflate group, in particular chlorine orbromine, X⁴ is a halogen atom selected from the group consisting ofchlorine, bromine and iodine, R⁶ is selected from the group consistingof OH, O⁻Na⁺, O⁻K⁺, O⁻Li⁺ and OR, where R is an unsubstituted alkylradical having 1 to 10 carbon atoms, and Y¹ and Y² are selected from thegroup consisting of CN, carboxylic acid, carboxylic anhydride orcarboxylic ester with a C1- to C10-alcohol.
 9. Process according to anyof claims 1 to 8, characterized in that R¹ has a structure of theformula (1)

in which R′ and R″ are hydrogen or fluorine or a methyl radical, L′ andL″ independently of one another are hydrogen, halogen, a substituted orunsubstituted branched or straight-chain alkyl, aryl or alkylaryl group,a substituted or unsubstituted branched or straight-chain alkoxy oraryloxy group, a substituted or unsubstituted branched or straight-chaincarboxyalkyl or carboxyaryl group, a nitro group or a trifluoromethylgroup, and Z is —P(CR′R″)_(o)— where P is oxygen or sulphur and o is aninteger from 0 to 4, m is an integer from 0 to 2, and n is an integerfrom 2 to
 8. 10. Process according to claim 9, characterized in that L′or L″ is hydrogen and the other substituent L′ or L″ is a halogen atom,m and o are 1, n is 6 and P is oxygen.
 11. Process according to any ofclaims 1 to 10, characterized in that the compound of the formula (VI)is proline or a derivative thereof.
 12. Process according to any ofclaims 1 to 11, characterized in that the compound of the formula (VI)is L-proline.
 13. Process for preparing oxiranecarboxylic acids andderivatives thereof, comprising the synthesis of a compound of theformula (IX), comprising the conversion of a compound of the formula(VIII) into the compound of the formula (IX)

where R¹ is a straight-chain or branched mono-, poly- or unsubstitutedalkyl group, a straight-chain or branched mono-, poly- or unsubstitutedalkylene group, a straight-chain or branched mono-, poly- orunsubstituted aralkyl, alkylaryl or aryl group, the radicals R⁴ and R⁵are identical or different straight-chain or branched mono-, poly- orunsubstituted alkyl groups, straight-chain or branched mono-, poly- orunsubstituted alkylene groups, straight-chain or branched mono-, poly-or unsubstituted aralkyl, alkylaryl or aryl groups, where R⁴NCR⁵ may bepart of a substituted or unsubstituted cyclic structure which may alsocontain a further heteroatom selected from the group consisting of N, Sand O, X⁴ is a functional group capable of forming a cationicintermediate in a reaction with a C—C double bond and is a good leavinggroup, and R¹ and R⁴NCR⁵ are not simultaneously —(CH₂)₆—OBn and anunsubstituted five-membered ring, respectively, and R⁶ is selected fromthe group consisting of OH, O⁻M⁺, O⁻M²⁺, where M is an alkali metal, analkaline earth metal or an earth metal or a cation of an organicnitrogen base, and OR, where R is a substituted or unsubstituted alkylor alkylene radical having 1 to 15 carbon atoms.
 14. Process forpreparing oxiranecarboxylic acids and derivatives thereof, comprisingthe synthesis of a compound of the formula (X), comprising a reaction ofa compound of the formula (IX) in which an oxirane of the formula (X) isformed

where R¹ is a straight-chain or branched mono-, poly- or unsubstitutedalkyl group, a straight-chain or branched mono-, poly- or unsubstitutedalkylene group, a straight-chain or branched mono-, poly- orunsubstituted aralkyl, alkylaryl or aryl group, R¹ is not —(CH₂)₆—OH, X⁴is a functional group capable of forming a cationic intermediate in areaction with a C—C double bond and is a good leaving group, and R⁶ isselected from the group consisting of OH, O⁻M⁺, O⁻M²⁺, where M is analkali metal, an alkaline earth metal or an earth metal or a cation ofan organic nitrogen base, and OR, where R is a substituted orunsubstituted alkyl or alkylene radical having 1 to 15 carbon atoms. 15.Process according to any of claims 1 to 12 or according to claim 13 oraccording to claim 14, characterized in that the individual reactionsteps are carried out under stereochemical control.
 16. Processaccording to any of claims 1 to 12 or according to claim 13 or accordingto claim 14 for preparing etomoxir, palmoxirate or clomoxir.
 17. Processaccording to any of claims 1 to 12 or according to claim 13 or accordingto claim 14 for preparing (+)-etomoxir.
 18. Compound, preparable by aprocess according to any of claims 1 to 12 or by a process according toclaim 13 or by a process according to claim
 14. 19. Compound, obtainableby step (a) of a process according to any of claims 1 to 12, having thegeneral formula

in which R′ is a straight-chain or branched mono-, poly- orunsubstituted alkyl group, a straight-chain or branched mono-, poly- orunsubstituted alkylene group, a straight-chain or branched mono-, poly-or unsubstituted aralkyl, alkylaryl or aryl group, the radicals R⁴ andR⁵ are identical or different straight-chain or branched mono-, poly- orunsubstituted alkyl groups, straight-chain or branched mono-, poly- orunsubstituted alkylene groups, straight-chain or branched mono-, poly-or unsubstituted aralkyl, alkylaryl or aryl groups, where R⁴NCR⁵ is partof a substituted or unsubstituted cyclic structure which may alsocontain a further heteroatom selected from the group consisting of N, Sand O.